Combination Cytotoxic-Differentiation Therapy of Mouse Erythroleukemia Cells with 5-Fluorouracil and Hexamethylene Bisacetamide

Samuel Waxman, Barbara M. Scher, Nella Hellinger, William Scher

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38 Scopus citations


The effects of 5-fluorouracil (5-FUra), in combination with various differentiation inducers on the growth and differentiation of mouse erythroleukemia (MEL) cells were investigated. The cells were first treated with 5-FUra, washed, and then treated with various concentrations of differentiation inducers: hexamethylene bisacetamide (HMBA), dimethyl sulfoxide (DMSO), and N-methylformamide. Pretreatment with 5-FUra, shown here to be a weak inducer of MEL cell differentiation, enhanced the subsequent HMBA induction of differentiation. The three inducers of differentiation markedly inhibited cell growth and increased cell death in a dose- and time-dependent manner if given immediately after cells were exposed to 5-FUra. In contrast, 5-FUra at similar concentrations inhibited cell growth, but only slightly increased cell death, while inducers without 5-FUra had little effect on cell growth or viability. When placed in fresh drug-free medium for 6 days following drug treatments, the cells completely recovered from the growth inhibition of 5-FUra as a single agent, whereas in cells previously treated with only HMBA there was a inhibition of cell growth without loss of viability. In contrast, a profound and prolonged growth inhibition with 98% cell death occurred in cells previously treated with 5-FUra followed by HMBA. The enhancement of 5-FUra cytotoxicity appeared to be directly related to the degree of differentiation and to biochemical events that occur during the commitment to terminal cell division induced by N-methylformamide, DMSO, or HMBA. An increase in Okazaki fragments was found in MEL cells treated with HMBA or DMSO when committed to terminal cell division. DNA breaks also follow 5-FUra treatment (A. Yoshioka et al., J. Biol. Chem., 262: 8235–8241, 1987) and may be the events that lead to cell death. The marked increase in cell death resulting from 5-FUra/HMBA treatment may be, at least partly, a consequence of increased DNA breaks due to 5-FUra followed by inhibition of DNA repair which is known to occur following the HMBA or DMSO induction of differentiation and commitment to terminal cell division. This combined sequential cytotoxic-differentiation therapy resulting in synergistic cytotoxicity and differentiation may be the basis of a new approach to cancer therapy and may aid in reducing the amounts of chemotherapeutic agents required for effective treatment, while maintaining or even increasing their therapeutic effects.

Original languageEnglish
Pages (from-to)3878-3887
Number of pages10
JournalCancer Research
Issue number13
StatePublished - 1 Jul 1990


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